Functional analysis and clinical application of linear ubiquitin signaling in lung cancer

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K14982
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Gunma University
• Principal Investigator: Nakazawa Seshiru 群馬大学, 医学部附属病院, 医員 (60791978)
• Research Collaborator: TOKUNAGA Fuminori ; KAIRA Kyoichi ; MOGI Akira ; SHIMIZU Kimihiro
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 肺癌

Outline of Final Research Achievements

We analyzed the potential role of linear ubiquitin and LUBAC as therapeutic targets of lung cancer. Components of LUBAC were related to lung cancer survival in specific histological types and similar cell lines showed high expression of LUBAC. Inhibition of LUBAC expression in cell lines with high LUBAC expression led to inhibition of NFKB activation and other signaling pathways related to lung cancer proliferation and migration. Inhibitors of LUBAC activity had similar effects on lung cancer cell lines and thus suggested that LUBAC and its components are potential targets of lung cancer therapy. We also identified lung cancer cases that had mutations of LUBAC at amino-acid residues related to enhanced activation of LUBAC and carcinogenesis.

Free Research Field

肺癌

Academic Significance and Societal Importance of the Research Achievements

肺癌は国内外で注目度の高い研究分野であるが、死亡率は依然高く、新規治療標的の同定が切望されている。またEGFR変異陽性肺癌が急増し、EGFR-TKIなど分子標的薬が著効する一方で、その耐性メカニズムの解明も重要である。本研究で直鎖状ユビキチンとその合成酵素LUBACがin vitroとin vivoで肺癌の治療標的として有用であることが明らかになった。また、本研究では肺癌が炎症性疾患を背景に発症する事から、LUBAC抑制により炎症を惹起するNFKB経路の抑制が可能となる事に加え、さらにEGFRなど他の腫瘍シグナル経路の活性化とLUBACの関与が明らかとなり、臨床的意義は深い。